JP2008501448A - Method and apparatus for determining parameters of biological tissue - Google Patents

Abstract

A device for measuring a glucose level or some other parameter of living tissue that affects the dielectric properties of the tissue is disclosed. The device comprises an electrode arrangement (5) having a plurality of electrodes (5-i). The signal from a signal source (31) can be applied to the electrode arrangement via a switching assembly (39). The switching assembly (39) is designed to selectively connect a first and a second pattern of the electrodes (5-i) to the signal source, thereby generating a first and a second electrical field with different spatial distribution in the tissue. By using a differential method which relies on measuring the impedance of the electrode arrangement (5) for each field and on suitable subtraction of the measured results, surface effects can be reduced and the focus of the measurement can be offset to a point deeper inside the tissue.

Description

  The present invention is not particularly limited to that purpose, but relates to a method and apparatus for determining dielectric properties of biological tissue for purposes such as measuring glucose in tissue.

  WO 02/069791 describes a device for measuring blood glucose in living tissue. The device includes an electrode device having a ground electrode and a signal electrode. The signal source supplies an electrical AC signal of known voltage or current through the resistor to the electrode and determines the voltage on the detector electrode. This is dependent on the dielectric properties of the tissue and indicates the glucose level in the tissue when it is discovered.

  Although this type of device is known to give good results, they require substantial labor for calibration, especially when environmental conditions change or when they are replaced. Easy to receive. In other technical fields, differential methods are used to improve the accuracy of the measurement. Differential methods are generally based on two or more measurements, in which one or more measurement conditions are changed between measurements. Depending on the particular application, the influence of some parameters can be eliminated or reduced by calculating the difference between measurements.

  Accordingly, it is a general object of the present invention to provide a method and apparatus of the type described above with improved accuracy.

  This object is achieved by a method and device according to the independent claims.

  That is, the device according to the present invention comprises an electrode device, a signal source, and a detector. This signal source supplies an electrical signal to the electrode device. The device is configured to generate at least two spatially different electric fields in the tissue. The detector measures the difference in tissue response to the electric field. This difference depends on the spatial difference between the electric fields, i.e. mainly according to the dielectric properties of the region in the tissue where the difference between the at least two spatially different electric fields is strongest.

  By appropriately selecting the spatial distribution of the electric field, it becomes possible to mainly measure the characteristics of the region of the tissue that cannot be selectively measured by using only a single electric field.

  In particular, a spatially different electric field is provided by an electrode device having at least three, preferably more electrodes, and first a first voltage pattern is supplied to the electrode device and then a second voltage pattern is provided to the electrodes And the first and second voltage patterns are different. This can be accomplished, for example, by placing a switching assembly between the signal source and the electrode, the switching assembly selectively connecting at least first and second patterns of electrodes to the signal source.

In an advantageous embodiment, two values s ₁ and s ₂ are measured, s ₁ indicating the tissue response to the first electric field, and s ₂ indicating the tissue response to the second electric field. The parameter is calculated from the weighted difference D = k ₁ · s ₁ −k ₂ · s ₂ , where k ₁ and k ₂ are weights. The weights k ₁ and k ₂ or the ratio k ₁ : k ₂ are less dependent on the response of the tissue whose weighted difference is close to the surface of the body (ie the epidermis), but the dermis-like body further away from the electrode Can be calculated in a calibration procedure under conditions primarily in accordance with the tissue response of deep regions inside. In other words, k ₁ and k ₂ are selected such that the effect of the tissue close to the electrode device on the weighted difference D (ie, the effect of the epidermis) is minimized, and in this context “minimized” is D It is understood that the effect on is much smaller than the individually measured values s ₁ and s ₂ , but does not have to be zero or an absolute minimum. This makes it possible to minimize unwanted effects (such as temperature and surface conditions etc.) that affect the characteristics of the body surface. The values s ₁ and s ₂ are real or complex quantities. If s ₁ and s ₂ are complex numbers, k ₁ and k ₂ are generally complex numbers as well.

  The device according to the invention is particularly suitable for measuring tissue glucose levels, but can also be used to measure any other parameter that affects the dielectric properties of the tissue, such as electrolyte levels.

The present invention is well understood and objects other than those described above will become apparent upon consideration of the following detailed description. Such description refers to the accompanying drawings.
FIG. 1 shows a cross-section of a device 200 for measuring a patient's body glucose level or some other parameter, such as tissue electrolyte levels. It comprises a housing 1 that is closed on one side by an electrode plate 2. The display 3 is disposed on the side opposite to the electrode plate 2. The electronic circuit is arranged between the electrode plate 2 and the display 3.

  The electrode plate 2 comprises a substrate 4 of electrically insulating material. The electrode device 5 includes a plurality of parallel strip electrodes 5-0, 5-1, 5-2, etc., and is covered with an insulating layer 6, and the electrode device 5 is disposed on the outer side 7 of the insulating substrate 4. The inner side 8 of the insulating substrate 4 can be covered with a ground electrode 8. A suitable feedthrough contact (not shown) connects the strip electrode 5-i to a contact pad located on the inner side 8.

  The first temperature sensor 15 is attached to the ground electrode 9 in a direct thermal contact state, and measures the first temperature T1.

  A conductor or spring 18 is provided to connect the ground electrode 9, the contact pad, and the first temperature sensor 15 to an electronic circuit disposed on a printed circuit board 19 forming an assembly of electronic components. . A battery 21 for energizing the circuit is arranged between the printed circuit board 19 and the electrode plate 2. The second temperature sensor 22 is disposed on the printed circuit board 19 and is in direct thermal contact therewith to measure the second temperature T2.

  FIG. 2 shows a block circuit diagram of the circuit of the device 100. It comprises a voltage controlled oscillator (VCO) 31 as a signal source for generating a sine wave signal or other periodic signal. Instead of an oscillator, a pulse generator can be used to generate a substantially aperiodic signal, such as a short pulse or stepped voltage transition. The signal from the signal source is provided to two amplifiers 32 and 33. The output of the first amplifier 32 is connected to the first signal path 34 via the resistor R1. A resonance circuit 35 constituted by an inductance L and a capacitive load in series of the electrode device 5 is connected between the first signal path 34 and the grounding point. The switching assembly 39 is used to selectively connect the strip electrode 5-i to inductance L or ground, as described below, thereby defining at least two different electrode patterns.

  The output of the second amplifier 33 is connected to the second signal path 36 via the resistor R2. The second signal path 36 can be substantially the same as the first signal path 34, but includes a resistor R3 as a reference load instead of the resonant circuit 35.

  Both signal paths 34, 36 are provided to a measurement circuit 37, which determines the relative amplitude A of both signals and / or their mutual phase shift φ. The relative amplitude A is, for example, the amplitude of the first signal path 34 in units of the amplitude of the second signal path (where the amplitude is the peak value of a sine wave, or a pulse or voltage step is used as the measurement signal) If used, the corresponding peak amplitude or step voltage).

  The output signal of the measurement circuit 37 is supplied to the microprocessor 38, which also controls the operation of the VCO 31.

  The microprocessor 38 further extracts the first and second temperature signals T1 and T2 from the first and second temperature sensors 15,22. It also controls the display device 3, an input device 40 having a control device operable by the user, and an interface 41 to an external computer. A memory 42 is provided for storing calibration parameters and measurement results, as well as data and microprocessor 38 firmware. At least a portion of the memory 42 is non-volatile.

  The inductance L of the device of FIG. 2 can be generated by the coil and / or the conductors and electrodes of the electrode device 5. Its value is usually known for reasonable accuracy.

  The electrode device 5 mainly represents a capacitive load C.

  The electrodes of the electrode device 5 are placed on the patient's skin 16 as shown in FIG. The device is either effectively worn on the arm or foot or provided with a suitable holding device or wrist band 43 for good and permanent contact with the patient's skin.

In summary, the device shown in FIGS. 1 and 2 is
An electrode device 5;
A signal source (VCO 31) for supplying an electrical signal to the electrode device 5 to generate an electric field in the tissue;
A response from the tissue response to the electric field is measured, from which at least one parameter is determined, comprising a detector comprising mainly elements 37 and 38.

  FIG. 3 shows the switching assembly 39 and the electrode device 5 in detail. As shown, each strip electrode 5-i of the electrode device 5 is connected to an electronic switch Si to selectively connect it to either ground or inductance L. The switch control device 45 is provided for individually controlling the position of each switch Si. The switch controller 45 is controlled by the microprocessor 38.

  In this embodiment, the switch controller 45 has two operation modes.

  In the first mode of operation (as indicated by the switch position in FIG. 3), the switch controller 45 connects the electrodes 5-0, 5-2, 5-4, 5-6 to the inductance L, which The switches S0, S2, S4, S6 are set so as to connect to the signal from the VCO 31, and the switches S1, S3, S5, S7 connect the electrodes 5-1, 5-3, 5-5, 5-7 to the ground potential. Set to connect to. In this first mode of operation, the voltage pattern supplied to the electrodes is therefore such that each pair of adjacent electrodes transmits a different voltage.

In the second mode of operation, the switches S0, S1, S4, S5 are set to connect the electrodes 5-0, 5-1, 5-4, 5-5 to the inductance L and to the signal from the VCO 31. On the other hand, the switches S2, S3, S6, and S7 are set so as to connect the electrodes 5-2, 5-3, 5-6, and 5-7 to the ground potential. In this mode of operation, the voltage pattern of the electrodes of the first part of the adjacent electrode pair transmits an equal voltage and the electrodes of the second part of the adjacent electrode pair transmit different voltages. As will be readily understood, the electric fields generated in the two modes of operation have different spatial distributions as shown by the curves e1, e2 in FIG. Any measured parameter s indicating the tissue response to a given electric field has different values s ₁ and s _{2 in the two} modes of operation, depending on how the electric field is distributed.

  In this context, we are particularly interested in how the measured parameter s depends on the dielectric properties of the epidermis close to the surface and how this depends on the dielectric properties of the dermis deeper in the tissue. Yes.

In the following description, it is assumed that the measured parameter s is the capacitance C _i of the electrode device 5 in a predetermined mode of operation i. For linear approximation, the following equation is given:

Here, the subscript “ep” indicates the effect from the epidermis, and “dr” indicates the effect from the dermis. The superscript “0” indicates a “normal” (undisturbed) value, for example, during a calibration measurement or for a typical subject. ε is the dielectric constant of the tissue in the dermis or epidermis, respectively. The derivative of C in terms of ε can be calculated, for example, from a typical tissue dielectric model. Similar dependence was measured for other factors, such as reverse resistance 1 / R between electrodes versus dermal and epidermal conductivity, or complex impedance Z as a function of both dermal and epidermal dielectric constant and conductivity. Observe also for the value. The measured value depends on the operating mode, i.e. according to the voltage pattern applied to the electrodes.

  In operation, the device 100 can be used, for example, to measure the capacitance C, resistance R, or complex impedance Z of the electrode device 5 at a frequency f of one or more. This impedance Z follows the dielectric response of the tissue to the applied electric field, and when it is discovered, this indicates the glucose concentration in the tissue.

  As known to those skilled in the art, capacitance C, resistance R, or complex impedance Z can be measured, for example, by determining the relative amplitude A and phase shift φ provided by measurement circuit 37.

Effectively, the microprocessor 38 calculates _two values s ₁ and s ₂ that indicate the dielectric response of the tissue to the first and second electric fields. If capacitances C ₁ and C ₂ during the first and second modes of operation are measured, s ₁ = C ₁ and s ₂ = C ₂ .

Subsequent calculation of the weighted difference effectively determines the difference in response to the two electric fields.
D ^C = k ₁ · C ₁ −k ₂ · C ₂ (2)
Here, the superscript C indicates that for the constants k ₁ and k ₂ for the capacitance measurement (similar equations with different constants can be obtained for the conductivity measurement, ie s = 1 / R), weights k ₁ and k ₂ are selected such that the non-constant influence of the skin dielectric properties on the difference D is substantially zero.

Combining equations (1) and (2) yields:

In order to minimize the effect of non-constant epidermis, the second square bracket in equation (3) must be zero. This can be achieved, for example, by optionally setting k ₁ ^C to 1 and using k ₂ ^C = (∂C ₁ / ∂ε _ep ) / (∂C ₂ / ∂ε _ep ).

Instead of optionally setting k ₁ ^C to 1, the constant is similarly affected by the “normal” value in the first square bracket of equation (3), and therefore the difference D is set to the dermis It can be chosen to depend only on the influence. In this case, setting the first and second square brackets of equation (3) to 0 yields a system of two equations that allows the values of k ₁ ^C and k ₂ ^C to be determined. After measuring the difference D and the temperatures T ₁ , T ₂ , the microprocessor 38 determines the glucose level g (or a parameter indicating it) from the measured input values D, T ₁ , T ₂ , for example of the following type: You can use the formula. Here, function F has M + 1 parameters a ₀ ,. . . a _M (M ≧ 0).

g = F (D, T ₁ , T ₂ , a ₀ ,... a _M ) (4)
The function F can be empirical or based at least in part on a model that describes the physical characteristics of the organs involved.

The relationship between the glucose level g and the measured value s _i is at least approximately linear and the following equation can be used:
When M = 3, g = a ₀ + a ₁ · D + a ₂ · T ₁ + a ₃ · T ₂ (5)
Parameters a ₀ , a ₁ ,. . . In order to determine a _M , a series of at least M + 1 calibration measurements must be performed, each calibration measurement being an input value D, T ₁ , T ₂ and a reference measured by conventional means, eg by intrusion methods Includes determination of glucose level g.

In most simple methods, the parameter a _i can then be obtained from a normal least squares fitting algorithm that varies the parameter a _i to find the best match of equation (4) or (5) for the calibration measurement. it can. Suitable algorithms are known to those skilled in the art and are described, for example, in publications (Teukolsky, Vetterling, Flannery, “Numerical Recipes in C”, Cambridge University Press, 2nd edition, 1992, Chapter 15).

Once the parameter a _i is known, the glucose level g can be determined from equation (4) or (5) based on the measurement of the input values D, T ₁ , T ₂ .

  Recalibration of at least some of the parameters will be wise after regular intervals or displacement of the device 100 with respect to the specimen.

  In the above example, the electrode device includes a plurality of strip-shaped electrodes arranged side by side. Although at least three electrodes are required to support at least two spatially different electrode patterns, the number of electrodes can vary. At least four, especially at least eight electrodes are effective to keep the fringe field effect small.

In different operating modes, the voltage pattern applied to the electrodes can be varied as well. In the above example, the following scheme was used. In the first mode of operation, voltage v _{i at} electrode _i was:
If i is even, v _i = v ₀ ,
Otherwise, v _i = 0 (6)
(Here, v ₀ indicates the voltage at the output of the inductance L). On the other hand, in the second operation mode, the voltage at the electrode i is:
If floor (i / 2) is even, v _i = v ₀ ,
Otherwise, v _i = 0 (7)
Here, if x is an integer value, floor (x) is equal to x, otherwise it is the next lower integer value.

  It should be noted that other patterns can be used as well. For example, the same voltage can be applied to three or more adjacent electrodes instead of two in the second operation mode. Furthermore, it is recommended that the outermost electrode always be connected to ground potential to ensure that it has a well-defined boundary state.

Other voltage patterns can be used as well. It is also possible to use more than two possible voltage levels in order to emphasize the difference in electric field far from the electrode, i.e. the difference in influence from the dermis. For example, in the second operation mode, the voltage at the electrode V _i can be selected as follows:
V _i = V ₀ · sin (i · π / k)
Here, k ≧ 2. For example, at k = 2, the voltage at electrode 0 is 0, the voltage at electrode 1 is V ₀ , the voltage at electrode 2 is 0, and the voltage at electrode 3 is −V ₀ , which is Compared to an electric field close to, an electric field at some distance from the electrode will increase.

  In general, any electrode device capable of generating at least two spatially different alternating electric fields in adjacent tissues can be used. “Spatially different” is used to describe electric fields having different shapes. It is not understood that electric fields that differ simply by multiplication factors are "spatially different".

  While the preferred embodiment of the invention has been illustrated and described, it should be clearly understood that the invention is not so limited and may be otherwise implemented and practiced within the scope of the appended claims. It is.

FIG. 3 is a cross-sectional view of an apparatus for measuring glucose levels. FIG. 2 is a block circuit diagram of the apparatus of FIG. 1. Detailed view of electrode device and switching assembly. FIG. 6 shows the normalized mean absolute electric field as a function of depth.

Claims (10)

In a device for measuring tissue parameters, particularly glucose levels, which affect the tissue response to an electric field,
An electrode device (5);
A signal source (31) for generating an electrical signal applied to the electrode device (5) to generate an electric field in the tissue;
A detector (37, 38) for measuring a response from the tissue to the electric field and determining at least one parameter therefrom;
The apparatus generates at least two spatially different electric fields (E ₁ , E ₂ ) in the tissue, and the detector determines the parameter from a difference in the tissue response to the spatially different electric fields. A device that is configured to. The electrode device (5) comprises at least three electrodes, the device first supplying a first voltage pattern to the electrode device (5-i) and then applying a second voltage pattern to the electrodes ( 5-i) configured to generate the at least two spatially different electric fields (E ₁ , E ₂ ), wherein the first and second voltage patterns are different. The apparatus according to 1.   In order to selectively connect at least the first and second patterns of the electrode (5-i) to the signal source (31), between the signal source (31) and the electrode (5-i) 3. An apparatus according to claim 2, comprising a switching assembly (39) arranged.   The device according to any one of claims 1 to 3, wherein the electrode device (5) comprises a plurality of electrodes (5-i) arranged side by side.   5. The device according to claim 4, wherein the electrode device (5) comprises four or more, in particular eight or more electrodes (5-i) arranged side by side. The device is optionally
In the first operation mode, the first voltage pattern is configured to be supplied to the electrode (5-i). In the first voltage pattern, each pair of adjacent electrodes has a different voltage. And
In the second operation mode, a second voltage pattern is configured to be supplied to the electrode (5-i), and in the second voltage pattern, the electrodes of the first portion of the pair of adjacent electrodes are equal. 6. A device according to claim 4 or 5, wherein the electrodes have a voltage and the electrodes of the second part of the pair of adjacent electrodes have different voltages. The detector (37, 38)
Measuring a first measured value s ₁ indicative of the tissue response to the first electric field and a second measured value s ₂ indicative of the tissue response to the second electric field; Composed of
The first and second electric fields are spatially different;
Configured to calculate a weighted difference k ₁ · s ₁ −k ₂ · s ₂ with weights k ₁ and k ₂ ;
7. Apparatus according to any one of the preceding claims, wherein the weighting is selected such that the non-constant influence of the dielectric response of the tissue epidermis on the weighted difference is minimized.   Said electrode arrangement (5) comprises a plurality of electrodes (5-i), said detector (37, 38) comprising at least two different combinations of capacitance (C) and / or resistance (R) and / or 8. The device according to claim 1, wherein the device is configured to measure a value according to impedance (Z).   9. A device according to any preceding claim, wherein the parameter is a glucose level in the tissue. In a method of measuring a tissue parameter affecting the tissue response to an electric field, in particular glucose level,
Providing an electrode device (5) for said tissue;
Providing a first electrical signal to the electrode device (5) for generating a first electric field in the tissue and detecting a first response of the tissue to the first electric field;
Generating a second electric field in the tissue, supplying a second electrical signal to the electrode device (5) for detecting a second response of the tissue to the second electric field, and And the second electric field is spatially different;
Determining the parameter from the difference between the first and second responses of the tissue.

Images